Department of Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA 91010; Department of Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010;
Department of Diabetes Research, Beckman Research Institute of City of Hope, Duarte, CA 91010; Department of Hematopoietic Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, CA 91010; Irell & Manella Graduate School of Biological Sciences of City of Hope, Duarte, CA 91010;
J Immunol. 2014 Aug 15;193(4):2005-15. doi: 10.4049/jimmunol.1401137. Epub 2014 Jul 7.
In nonautoimmune recipients, induction of mixed and complete chimerism with hematopoietic progenitor cells from MHC (HLA)-matched or -mismatched donors are effective approaches for induction of organ transplantation immune tolerance in both animal models and patients. But it is still unclear whether this is the case in autoimmune recipients. With the autoimmune diabetic NOD mouse model, we report that, although mixed and complete MHC-mismatched chimerism provide immune tolerance to donor-type islet and skin transplants, neither mixed nor complete MHC-matched chimerism does. The MHC-mismatched chimerism not only tolerizes the de novo developed, but also the residual pre-existing host-type T cells in a mismatched MHC class II-dependent manner. In the MHC-mismatched chimeras, the residual host-type peripheral T cells appear to be anergic with upregulation of PD-1 and downregulation of IL-7Rα. Conversely, in the MHC-matched chimeras, the residual host-type peripheral T cells manifest both alloreactivity and autoreactivity; they not only mediate insulitis and sialitis in the recipient, but also reject allogeneic donor-type islet and skin grafts. Interestingly, transgenic autoreactive BDC2.5 T cells from Rag1(+/+), but not from Rag1(-/-), NOD mice show alloreactivity and mediate both insulitis and rejection of allografts. Taken together, MHC-mismatched, but not MHC-matched, chimerism can effectively provide transplantation immune tolerance in autoimmune recipients.
在非自身免疫接受者中，用来自 MHC（HLA）匹配或不匹配供体的造血祖细胞诱导混合和完全嵌合是在动物模型和患者中诱导器官移植免疫耐受的有效方法。但在自身免疫接受者中是否如此仍不清楚。我们用自身免疫性糖尿病 NOD 小鼠模型报告说，尽管混合和完全 MHC 不匹配嵌合提供了对供体型胰岛和皮肤移植物的免疫耐受，但混合和完全 MHC 匹配嵌合都没有。MHC 不匹配嵌合体不仅以 MHC Ⅱ类依赖性方式耐受新开发的，而且耐受残留的先前存在的宿主型 T 细胞。在 MHC 不匹配嵌合体中，残留的宿主型外周 T 细胞似乎呈无反应性，PD-1 上调，IL-7Rα 下调。相反，在 MHC 匹配嵌合体中，残留的宿主型外周 T 细胞表现出同种反应性和自身反应性；它们不仅介导受体内的胰岛炎和唾液腺炎，而且还排斥同种异体供体型胰岛和皮肤移植物。有趣的是，来自 Rag1(+/+)而非 Rag1(-/-)NOD 小鼠的转基因自身反应性 BDC2.5 T 细胞表现出同种反应性，并介导胰岛炎和同种异体移植物排斥。总之，MHC 不匹配，但不是 MHC 匹配，嵌合可以有效地为自身免疫接受者提供移植免疫耐受。
